Neurostimulation with signal duration determined by a cardiac cycle

ABSTRACT

We disclose a method of providing an electrical signal to a cranial nerve of a patient for treating a medical condition, comprising providing an electrical signal generator, coupling at least a first electrode to a cranial nerve of the patient and to the electrical signal generator, generating an electrical signal with the electrical signal generator, and applying the electrical signal to the cranial nerve, using the at least a first electrode, for a duration less than a cardiac period of the patient and during the cardiac period of the patient. We also disclose an implantable medical device capable of implementing the method.

BACKGROUND OF THE INVENTION

This invention relates generally to medical device systems and, more particularly, to medical device systems for applying electrical signals to a cranial nerve for the treatment of various medical conditions at particular times and for particular durations determined by a patient's cardiac cycle.

Many advancements have been made in treating diseases such as depression and epilepsy. Therapies using electrical signals for treating these diseases have been found to effective. Implantable medical devices (IMDs) have been effectively used to deliver therapeutic stimulation to various portions of the human body (e.g., the vagus nerve) for treating these diseases. As used herein, “stimulation” or “stimulation signal” refers to the application of an electrical, mechanical, magnetic, electromagnetic, photonic, audio and/or chemical signal to a neural structure in the patient's body. The signal is an exogenous signal that is distinct from the endogenous electrical, mechanical, and chemical activity (e.g., afferent and/or efferent electrical action potentials) generated by the patient's body and environment. In other words, the stimulation signal (whether electrical, mechanical, magnetic, electromagnetic, photonic, audio or chemical in nature) applied to the nerve in the present invention is a signal applied from an artificial source, e.g., a neurostimulator.

A “therapeutic signal” refers to a stimulation signal delivered to a patient's body with the intent of treating a medical condition by providing a modulating effect to neural tissue. The effect of a stimulation signal on neuronal activity is termed “modulation”; however, for simplicity, the terms “stimulating” and “modulating”, and variants thereof, are sometimes used interchangeably herein. In general, however, the delivery of an exogenous signal itself refers to “stimulation” of the neural structure, while the effects of that signal, if any, on the electrical activity of the neural structure are properly referred to as “modulation.” The modulating effect of the stimulation signal upon the neural tissue may be excitatory or inhibitory, and may potentiate acute and/or long-term changes in neuronal activity. For example, the “modulating” effect of the stimulation signal to the neural tissue may comprise one more of the following effects: (a) initiation of an action potential (afferent and/or efferent action potentials); (b) inhibition or blocking of the conduction of action potentials, whether endogenous or exogenously induced, including hyperpolarizing and/or collision blocking, (c) affecting changes in neurotransmitter/neuromodulator release or uptake, and (d) changes in neuro-plasticity or neurogenesis of brain tissue.

In some embodiments, electrical neurostimulation may be provided by implanting an electrical device underneath the skin of a patient and delivering an electrical signal to a nerve such as a cranial nerve. In one embodiment, the electrical neurostimulation involves sensing or detecting a body parameter, with the electrical signal being delivered in response to the sensed body parameter. This type of stimulation is generally referred to as “active,” “feedback,” or “triggered” stimulation. In another embodiment, the system may operate without sensing or detecting a body parameter once the patient has been diagnosed with a medical condition that may be treated by neurostimulation. In this case, the system may apply a series of electrical pulses to the nerve (e.g., a cranial nerve such as a vagus nerve) periodically, intermittently, or continuously throughout the day, or over another predetermined time interval. This type of stimulation is generally referred to as “passive,” “non-feedback,” or “prophylactic,” stimulation. In yet another type of stimulation, both passive stimulation and feedback stimulation be combined, in which electrical signals are delivered passively according to a predetermined duty cycle, and also in response to a sensed body parameter. The electrical signal may be applied by a pulse generator that is implanted within the patient's body. In another alternative embodiment, the signal may be generated by an external pulse generator outside the patient's body, coupled by an RF or wireless link to an implanted electrode or an external transcutaneous neurostimulator (TNS).

Generally, neurostimulation signals that perform neuromodulation are delivered by the IMD via one (i.e., unipolar) or more (i.e., bipolar) leads. The leads generally terminate at their distal ends in one or more electrodes, and the electrodes, in turn, are electrically coupled to tissue in the patient's body. For example, a number of electrodes may be attached to various points of a nerve or other tissue inside or outside a human body for delivery of a neurostimulation signal.

Conventional vagus nerve stimulation (VNS) usually involves non-feedback stimulation characterized by a number of parameters. Specifically, conventional vagus nerve stimulation usually involves a series of electrical pulses in bursts defined by an “on-time” and an “off-time.” During the on-time, electrical pulses of a defined electrical current (e.g., 0.5-2.0 milliamps) and pulse width (e.g., 0.25-1.0 milliseconds) are delivered at a defined frequency (e.g., 20-30 Hz) for the on-time duration, usually a specific number of seconds, e.g., 7-60 seconds. The pulse bursts are separated from one another by the off-time, (e.g., 14 seconds-5 minutes) in which no electrical signal is applied to the nerve. The on-time and off-time parameters together define a duty cycle, which is the ratio of the on-time to the sum of the on-time and off-time, and which describes the percentage of time that the electrical signal is applied to the nerve. It will be appreciated that calculation of duty cycle should also include any ramp-up and/or ramp-down time.

In conventional VNS, the on-time and off-time may be programmed to define an intermittent pattern in which a repeating series of electrical pulse bursts are generated and applied to the vagus nerve 127. Each sequence of pulses during an on-time may be referred to as a “pulse burst.” The burst is followed by the off-time period in which no signals are applied to the nerve. The off-time is provided to allow the nerve to recover from the stimulation of the pulse burst, and to conserve power. If the off-time is set at zero, the electrical signal in conventional VNS may provide continuous stimulation to the vagus nerve. Alternatively, the idle time may be as long as one day or more, in which case the pulse bursts are provided only once per day or at even longer intervals. Typically, however, the ratio of “off-time” to “on-time” may range from about 0.5 to about 10.

Although neurostimulation has proven effective in the treatment of a number of medical conditions, including epilepsy, it would be desirable to further enhance and optimize a therapeutic regimen comprising neurostimulation for this purpose. For example, it may be desirable to collect other data, either directly or indirectly associated with an acute incident of the medical condition, in order to inform the patient and/or his physician about the severity, progression, or remission of the medical condition. To do so, it may be desirable to provide a neurostimulation off-time during which the other data may be collected.

SUMMARY OF THE INVENTION

In one embodiment, the present invention relates to a method of providing an electrical signal to a cranial nerve of a patient for treating a medical condition, comprising providing an electrical signal generator, coupling at least a first electrode to a cranial nerve of the patient and to the electrical signal generator, generating an electrical signal with the electrical signal generator, and applying the electrical signal to the cranial nerve using the at least first electrode, wherein said electrical signal is applied to the cranial nerve for a duration determined by a cardiac cycle parameter of the patient. In one embodiment, the cardiac cycle parameter of the patient may comprise an R-R interval, another interbeat interval of the patient's cardiac cycle, or cardiac cycle components such as a P wave interval, a PR segment interval, a PQ segment interval, a QRS interval, or an ST segment interval. In another embodiment, applying the electrical signal to the cranial nerve is initiated at a time determined by a cardiac cycle parameter of the patient.

In another embodiment, in a method of providing an electrical signal to a cranial nerve of a patient for treating a medical condition, the present invention relates to the improvement comprising providing the electrical signal to the cranial nerve, wherein said electrical signal is applied to the cranial nerve for a duration determined by a cardiac cycle parameter of the patient.

In an additional embodiment, the present invention relates to an implantable medical device (IMD) comprising an electrical signal generator; a first electrode and a second electrode operatively coupled to the electrical signal generator; and a cardiac cycle determination module capable of determining a cardiac cycle of a patient; wherein: the electrical signal generator is capable of generating and delivering at least one electrical signal through at least one of the first electrode and the second electrode, wherein applying said electrical signal is applied to the cranial nerve for a duration determined by a cardiac cycle parameter of the patient.

In one embodiment, the present invention relates to a method of providing an electrical signal to a cranial nerve of a patient for treating a medical condition, comprising providing an electrical signal generator, coupling at least a first electrode to a cranial nerve of the patient and to the electrical signal generator, generating an electrical signal with the electrical signal generator, and applying the electrical signal to the cranial nerve, using the at least a first electrode, for a duration determined by a cardiac cycle of the patient. In a further embodiment, the method further comprises beginning to apply said electrical signal at a predetermined time in the cardiac cycle of the patient. The predetermined time may follow a delay period following detection of an R-wave in the cardiac cycle of the patient, or may comprise a predetermined multiple of an interbeat interval in the cardiac cycle of the patient.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention may be understood by reference to the following description taken in conjunction with the accompanying drawings, in which like reference numerals identify like elements, and in which:

FIGS. 1A-1C provide stylized diagrams of an implantable medical device implanted into a patient's body for providing an electrical signal to a portion of the patient's body, in accordance with one illustrative embodiment of the present invention;

FIG. 2 illustrates a block diagram depiction of the implantable medical device of FIG. 1, in accordance with one illustrative embodiment of the present invention;

FIG. 3A illustrates an exemplary waveform sequence of a cardiac cycle of a human being as measured by an electrocardiogram (EKG);

FIG. 3B illustrates a block diagram depiction of a cardiac cycle determination module of the implantable medical device of FIG. 2; and

FIG. 4 illustrates a flowchart depiction of a method in accordance with an illustrative embodiment of the present invention.

While the invention is susceptible to various modifications and alternative forms, specific embodiments thereof have been shown by way of example in the drawings and are herein described in detail. It should be understood, however, that the description herein of specific embodiments is not intended to limit the invention to the particular forms disclosed, but on the contrary, the intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the invention as defined by the appended claims.

Description of Illustrative Embodiments

Illustrative embodiments of the invention are described herein. In the interest of clarity, not all features of an actual implementation are described in this specification. In the development of any such actual embodiment, numerous implementation-specific decisions must be made to achieve the design-specific goals, which will vary from one implementation to another. It will be appreciated that such a development effort, while possibly complex and time-consuming, would nevertheless be a routine undertaking for persons of ordinary skill in the art having the benefit of this disclosure.

This document does not intend to distinguish between components that differ in name but not function. In the following discussion and in the claims, the terms “including” and “includes” are used in an open-ended fashion, and thus should be interpreted to mean “including, but not limited to.” Also, the term “couple” or “couples” is intended to mean either a direct or an indirect electrical connection. “Direct contact,” “direct attachment,” or providing a “direct coupling” indicates that a surface of a first element contacts the surface of a second element with no substantial attenuating medium there between. The presence of small quantities of substances, such as bodily fluids, that do not substantially attenuate electrical connections does not vitiate direct contact. The word “or” is used in the inclusive sense (i.e., “and/or”) unless a specific use to the contrary is explicitly stated.

The term “electrode” or “electrodes” described herein may refer to one or more stimulation electrodes (i.e., electrodes for delivering an electrical signal generated by an IMD to a tissue), sensing electrodes (i.e., electrodes for sensing a physiological indication of a patient's body), and/or electrodes that are capable of delivering a stimulation signal, as well as performing a sensing function.

“Cardiac cycle” refers to one complete PQRSTU interval of the patient's heart functioning, ending with the P wave of the next succeeding cardiac cycle. “Interbeat interval” refers to the time period between a predetermined point in a first cardiac cycle of the patient and the same predetermined point in the immediately succeeding cardiac cycle of the patient, for example an R-R interval, a P-P interval, or a T-T interval. Interbeat intervals may comprise a single interval or a moving average (either simple or weighted) of several consecutive intervals. “Cardiac period” is a length of time between a first point in the cardiac cycle of the patient and a second, later point. Exemplary points include a P-wave, a Q-wave, an R-wave, an S-wave, a T-wave, and a U-wave of the cardiac cycle, which can be readily identified by electrocardiography (EKG) or other techniques of monitoring the electrical activity of the heart.

Cranial nerve stimulation has been proposed to treat a number of medical conditions pertaining to or mediated by one or more structures of the nervous system of the body, including epilepsy and other movement disorders, depression, anxiety disorders and other neuropsychiatric disorders, dementia, head trauma and traumatic brain injury, coma, obesity, eating disorders, sleep disorders, cardiac disorders (such as congestive heart failure and atrial fibrillation), hypertension, endocrine disorders (such as diabetes and hypoglycemia), and pain syndromes (including migraine headache and fibromyalgia), among others. See, e.g., U.S. Pat. Nos. 4,867,164; 5,299,569; 5,269,303; 5,571,150; 5,215,086; 5,188,104; 5,263,480; 6,587,719; 6,609,025; 5,335,657; 6,622,041; 5,916,239; 5,707,400; 5,231,988; and 5,330,515. Despite the numerous disorders for which cranial nerve stimulation has been proposed or suggested as a treatment option, the fact that detailed neural pathways for many (if not all) cranial nerves remain relatively unknown, makes predictions of efficacy for any given disorder difficult or impossible. Moreover, even if such pathways were known, the precise stimulation parameters that would modulate particular pathways relevant to a particular disorder generally cannot be predicted.

In one embodiment, the present invention provides a method of treating a medical condition. The medical condition can be selected from the group consisting of epilepsy, neuropsychiatric disorders (including but not limited to depression), eating disorders/obesity, traumatic brain injury/coma, addiction disorders, dementia, sleep disorders, pain, migraine, fibromyalgia, endocrine/pancreatic disorders (including but not limited to diabetes), motility disorders, hypertension, congestive heart failure/cardiac capillary growth, hearing disorders, angina, syncope, vocal cord disorders, thyroid disorders, pulmonary disorders, and reproductive endocrine disorders (including infertility). In a particular embodiment, the medical condition is epilepsy.

The implantable medical device (IMD) system of one embodiment of the present invention provides for software module(s) that are capable of acquiring, storing, and processing various forms of data, such as patient data/parameters (e.g., physiological data, side-effects data, such as heart rate, breathing rate, brain-activity parameters, disease progression or regression data, quality of life data, etc.) and therapy parameter data. Therapy parameters may include, but are not limited to, electrical signal parameters that define the therapeutic electrical signals delivered by the IMD, medication parameters and/or any other therapeutic treatment parameter. In an alternative embodiment, the term “therapy parameters” may refer to electrical signal parameters defining the therapeutic electrical signals delivered by the IMD. Therapy parameters for a therapeutic electrical signal may also include, but are not limited to, a current amplitude, a pulse width, an interburst period, a number of pulses per burst, an interpulse interval, a burst duration, an on-time, and an off-time.

In one embodiment of the present invention, an electrical signal may be provided in a duration that is determined as a function of a physiological cycle, e.g., a cardiac cycle. In one embodiment, the duration may be less than the physiological cycle, e.g., less than a cardiac cycle of the patient. In this manner, data relating to a parameter associated with the physiological cycle may be collected at times when the electrical signal is not provided. For example, by providing electrical signals to a vagus nerve 10 msec after detection of an R-wave in a patient's cardiac cycle, for a duration that is less than the prior cardiac cycle, it may be possible to sense the next R-wave without interference that may be associated with a signal applied for a duration longer than the patient's cardiac cycle. While techniques are available that would permit overlapping stimulation and sensing (such as blanking intervals in the signal, or use of separate sensing and stimulation electrodes), use of certain embodiments of the present invention renders such techniques unnecessary, and permits a simpler design. Even where stimulation durations longer than the cardiac cycle are used, the present invention may still allow the timing of later heartbeats to be predicted with sufficient accuracy (based on, for example, a moving average heartbeat) to avoid the use of separate sensing and stimulation electrodes.

Although not so limited, a system capable of implementing embodiments of the present invention is described below. FIG. 1 depicts a stylized implantable medical system (IMD) 100 for implementing one or more embodiments of the present invention. An electrical signal generator 110 is provided, having a main body 112 comprising a case or shell with a header 116 for connecting to an insulated, electrically conductive lead assembly 122. The generator 110 is implanted in the patient's chest in a pocket or cavity formed by the implanting surgeon just below the skin (indicated by a dotted line 145), similar to the implantation procedure for a pacemaker pulse generator.

A nerve electrode assembly 125, preferably comprising a plurality of electrodes having at least an electrode pair, is conductively connected to the distal end of the lead assembly 122, which preferably comprises a plurality of lead wires (one wire for each electrode). Each electrode in the electrode assembly 125 may operate independently or alternatively, may operate in conjunction with the other electrodes. In one embodiment, the electrode assembly 125 comprises at least a cathode and an anode. In another embodiment, the electrode assembly comprises one or more unipolar electrodes with the return electrode comprising a portion of the generator 110.

Lead assembly 122 is attached at its proximal end to connectors on the header 116 of generator 110. The electrode assembly 125 may be surgically coupled to the vagus nerve 127 in the patient's neck or at another location, e.g., near the patient's diaphragm or at the esophagus/stomach junction. Other (or additional) cranial nerves such as the trigeminal and/or glossopharyngeal nerves may also be used as a target for the electrical signal in particular alternative embodiments. In one embodiment, the electrode assembly 125 comprises a bipolar stimulating electrode pair 126, 128 (i.e., a cathode and an anode). Suitable electrode assemblies are available from Cyberonics, Inc., Houston, Tex., USA as the Model 302 electrode assembly. However, persons of skill in the art will appreciate that many electrode designs could be used in the present invention. In one embodiment, the two electrodes are wrapped about the vagus nerve, and the electrode assembly 125 may be secured to the vagus nerve 127 by a spiral anchoring tether 130 such as that disclosed in U.S. Pat. No. 4,979,511 issued Dec. 25, 1990 to Reese S. Terry, Jr. and assigned to the same assignee as the instant application. Lead assembly 122 may be secured, while retaining the ability to flex with movement of the chest and neck, by a suture connection to nearby tissue (not shown).

In alternative embodiments, the electrode assembly 125 may comprise temperature sensing elements and/or heart rate sensor elements. Other sensors for other body parameters may also be employed to trigger active stimulation. For example, motion sensors or electrodes may be used to sense respiration, and pressure sensors or neural activity may be used to sense blood pressure. Both passive and active stimulation may be combined or delivered by a single IMD according to the present invention. Either or both modes may be appropriate to treat a specific patient under observation.

In alternative embodiments, a sensor assembly, comprising a sensor lead assembly and a sensor, may be employed to detect a body parameter of the patient.

The electrical pulse generator 110 may be programmed with an external device (ED) such as computer 150 using programming software known in the art. A programming wand 155 may be coupled to the computer 150 as part of the ED to facilitate radio frequency (RF) communication between the computer 150 and the pulse generator 110. The programming wand 155 and computer 150 permit non-invasive communication with the generator 110 after the latter is implanted. In systems where the computer 150 uses one or more channels in the Medical Implant Communications Service (MICS) bandwidths, the programming wand 155 may be omitted to permit more convenient communication directly between the computer 150 and the pulse generator 110.

The therapeutic electrical stimulation signal described herein may be used to treat a medical condition separately or in combination with another type of treatment. For example, electrical signals according to the present invention may be applied in combination with a chemical agent, such as various drugs, to treat various medical conditions. Further, the electrical stimulation may be performed in combination with treatment(s) relating to a biological or chemical agent. The electrical stimulation treatment may also be performed in combination with other types of treatment, such as magnetic stimulation treatment.

Turning now to FIG. 2, a block diagram depiction of the IMD 200 is provided, in accordance with one illustrative embodiment of the present invention. The IMD 200 (such as generator 110 from FIG. 1) may comprise a controller 210 capable of controlling various aspects of the operation of the IMD 200. The controller 210 is capable of receiving internal data or external data and causing a stimulation unit 220 to generate and deliver an electrical signal to target tissues of the patient's body for treating a medical condition. For example, the controller 210 may receive manual instructions from an operator externally, or may cause the electrical signal to be generated and delivered based on internal calculations and programming. The controller 210 is capable of affecting substantially all functions of the IMD 200.

The controller 210 may comprise various components, such as a processor 215, a memory 217, etc. The processor 215 may comprise one or more microcontrollers, microprocessors, etc., capable of performing various executions of software components. The memory 217 may comprise various memory portions where a number of types of data (e.g., internal data, external data instructions, software codes, status data, diagnostic data, etc.) may be stored. The memory 217 may comprise one or more of random access memory (RAM) dynamic random access memory (DRAM), electrically erasable programmable read-only memory (EEPROM), flash memory, etc.

The IMD 200 may also comprise a stimulation unit 220 capable of generating and delivering electrical signals to one or more electrodes via leads. A lead assembly such as lead assembly 122 (FIG. 1) may be coupled to the IMD 200. Therapy may be delivered to the leads comprising the lead assembly 122 by the stimulation unit 220 based upon instructions from the controller 210. The stimulation unit 220 may comprise various circuitry, such as electrical signal generators, impedance control circuitry to control the impedance “seen” by the leads, and other circuitry that receives instructions relating to the delivery of the electrical signal to tissue. The stimulation unit 220 is capable of delivering an electrical signal over the leads comprising the lead assembly 122. It will be appreciated by persons of skill in the art that some embodiments of the invention may comprise leadless stimulators such as injectable microstimulators.

The IMD 200 may also comprise a power supply 230. The power supply 230 may comprise a battery, voltage regulators, capacitors, etc., to provide power for the operation of the IMD 200, including delivering the therapeutic electrical signal. The power supply 230 comprises a power source that in some embodiments may be rechargeable. In other embodiments, a non-rechargeable power source may be used. The power supply 230 provides power for the operation of the IMD 200, including electronic operations and the electrical signal generation and delivery functions. The power supply 230 may comprise a lithium/thionyl chloride cell or a lithium/carbon monofluoride (LiCFx) cell. Other battery types known in the art of implantable medical devices may also be used.

The IMD 200 may also comprise a communication unit 260 capable of facilitating communications between the IMD 200 and various devices. In particular, the communication unit 260 is capable of providing transmission and reception of electronic signals to and from an external unit 270, such as computer 150 and wand 155 that may comprise an ED (FIG. 1). The communication unit 260 may include hardware, software, firmware, or any combination thereof.

In one embodiment, the IMD 200 may also comprise a sensor 295 that is capable of detecting various patient parameters. For example, the sensor 295 may comprise hardware, software, or firmware that is capable of obtaining and/or analyzing data relating to one or more body parameters of the patient. Based upon the data obtained by the detection unit 295, the IMD 200 may deliver or may refrain from delivering the electrical signal to a portion of the cranial nerve to treat epilepsy, depression or other medical conditions. In one embodiment, the sensor 295 may be capable of detecting a feedback response from the patient. The feedback response may include a magnetic signal input, a tap input, a wireless data input to the IMD 200, etc. The feedback may be indicative of a pain and/or noxious threshold, wherein the threshold may be the limit of tolerance of discomfort for a particular patient. The term “patient parameters” may refer to, but is not limited to, various body parameters, which may in some embodiments involve sensors coupled to the IMD 200.

In another embodiment, the sensor 295 may be capable of sensing at least one parameter of a cardiac cycle of the patient. In a further embodiment, the at least one cardiac cycle parameter is selected from the group consisting of a P-wave, a Q-wave, an R-wave, an S-wave, a T-wave, and a U-wave, or intervals associated with the foregoing such as an R-R interval or another interbeat interval such as a T-T interval, a P-wave interval, a PR segment interval, a PQ segment interval, a QRS interval, an ST segment interval. However, in another embodiment, a separate sensor 295 is not included, and sensing at least one parameter of a cardiac cycle of the patient may be performed via one or more of the electrodes 125(1), 125(2) and/or the shell 112 of the IMD 200.

In another embodiment, the sensor 295 may comprise hardware, software, or firmware that is capable of obtaining and/or analyzing data relating to the patient's cardiac cycle. Based upon the data obtained by the detection unit 295, the IMD 200 may deliver the electrical signal to a portion of the cranial nerve to treat epilepsy, depression or other medical conditions.

In one particular embodiment, sensing is performed using the at least one electrode. In a further embodiment, the IMD 200 comprises an electrical signal generator; and a first electrode and a second electrode operatively coupled to the electrical signal generator and a cranial nerve of the patient; wherein: the electrical signal generator is capable of generating and delivering at least one electrical signal through at least one of the first electrode and the second electrode to the cranial nerve, when not delivering the electrical signal, at least one of the first electrode and the second electrode is capable of detecting the patient's heartbeat. Any point in the patient's cardiac cycle can be observed in order to detect the patient's heartbeat. In one embodiment, the patient's heartbeat is detected by detecting an R-wave.

In some embodiments, bipolar or unipolar stimulation can be interleaved with heartbeat detection. In one embodiment, during a first time period an electrical signal generated by the electrical signal generator is applied to the cranial nerve using both the first electrode and the second electrode. During a second time period following the first time period, the first and second electrodes are capable of detecting the patient's heartbeat, and the electrical signal generator does not apply the electrical signal to the cranial nerve. As an illustrative example, the first time period may begin from about 10 msec to about 3000 msec after a first heartbeat of the patient. The second time period follows the first time period and extends from the end of the first time period until detection of another heartbeat and application of the electrical to the cranial nerve following the detection. The first time period may be preceded by a delay time period following detection of a heartbeat (for example by detection of an R-wave) and before application of the electrical signal to the cranial nerve.

In one embodiment, the first time period defining the duration of the electrical signal being applied to the nerve may comprise a predetermined fraction of the cardiac cycle time of the patient. For example, the electrical signal generator may be programmed to apply the electrical signal to the nerve for a time equal to 10% of the moving average of the most recent n heartbeats (where n is an integer from 2 to 100, inclusive, such as an integer from 2 to 10, inclusive) as measured by the R-R interval, or 50% of the most recent single R-R interval. It will be appreciated that the duration could vary from as little as 0.1% of the cardiac cycle time, to times exceeding 100% of the cardiac cycle time, for example 250% of the cardiac cycle time. In a preferred embodiment, the cycle time would range from 1% to 50% of the cardiac cycle time, to permit adequate time for the IMD to cease applying the electrical signal and to detect the next heartbeat without electrical interference from the electrical signal itself. By defining the first time period as a percentage of the cardiac cycle time, the IMD system can provide a system with a well-defined duty cycle that automatically adjusts itself to changes in the patient's heart rate, without compromising the ability of the system to detect a heartbeat and/or determine a heart rate by interference from the electrical signal. In embodiments where separate sensing and stimulation electrodes are provided, first time periods greater than 100% of the cardiac signal may be employed without compromising the ability to detect a heartbeat and/or determine a heart rate.

Where a delay interval is used following detection of a heartbeat prior to the application of the signal during the first time period, the delay period may comprise either a fixed time period that may range from 1 μsec to 3000 msec, preferably from 5 msec to about 250 msec, or a programmable percentage of a moving average or single heartbeat interval. For example, the device may be programmed to provide a delay period equal to 5% of the moving average of the most recently detected R-R intervals.

The IMD 200 of this embodiment can further comprise a cardiac cycle determination module 296 capable of calculating the patient's heart rate. In one embodiment, the heart rate is calculated from the R-R interval of successive cardiac cycles. In a further embodiment, the electrical signal generator is capable of adjusting at least one parameter defining the electrical signal in response to the patient's heart rate. These adjustments may include adjusting at least one parameter associated with the electrical signal, e.g., a current amplitude, a pulse width, an interburst period, a number of pulses per burst, an interpulse interval, a burst duration, an on-time, and an off-time.

An illustrative embodiment of the cardiac cycle determination module 296 is shown in FIG. 3B. A signal from the sensor is delivered to one or more of a P-wave detector 302, an R-wave detector 304, a T-wave detector 306, a QT interval detector 308, or an R-R interval detector 310. The various detectors 302-310 communicate with the heart beat characterization unit 320, which takes data from the detectors 302-310 and characterizes whether a heart beat has taken place. The heart rate determination unit 330 can then track characterizations of heart beats and their times to determine a heart rate, either instantaneously (between two consecutive heart beats) or as an average, for example, a moving average of the last n heart beats, where n is an integer from 2 to 100, inclusive. In one further embodiment, n is an integer from 2 to 10, inclusive.

In a further embodiment, the cardiac period determination module 296 calculates an interbeat interval (either a single R-R interval or a moving average) and the electrical signal is applied to the target cranial nerve for a predetermined multiple (e.g., 0.1% to 3000%) of the calculated interbeat interval, optionally following a delay period that may be a fixed time period or a time period likewise defined as a predetermined multiple (e.g., 1-20%) of the calculated interbeat interval. Instead of defining a delay period and a first time period as a multiple of the calculated interbeat interval, the beginning and ending timepoints of the first time period can equivalently be selected as occurred at selected points within the calculated interbeat interval following the detected heartbeat. For example, the stimulation can be programmed to begin at a timepoint that is 5% of the calculated interbeat interval following the detection of the heartbeat, and to end at a timepoint that is 15% of the calculated interbeat interval following detection of the heartbeat. In another embodiment, the stimulation may be synchronized with the detection of a P wave, a T wave, or other points within the cardiac cycle, such as beginning at the T wave detection and extending for a duration that is, for example, 20% of the calculated interbeat interval.

In one embodiment, the first time period has a duration of from about 5% to about 50% of the calculated interbeat interval. The first time period is followed by a second time period during which the IMD senses the next heartbeat, recalculates the interbeat interval, and again applies the electrical signal to the nerve for a predetermined percentage of the recalculated interbeat interval.

Although the above description is in the context of bipolar stimulation, the person of ordinary skill in the art, having the benefit of the present disclosure, will understand the IMD 200 may also or alternatively be capable of detecting a heartbeat during unipolar stimulation.

The characteristic of the cardiac cycle, after which initiation of delivery of the electrical signal is initiated, may be varied during operation of the IMD 200.

In one embodiment, the IMD 200 may comprise a cardiac cycle determination module 296. The cardiac cycle determination module 296 may be capable of analyzing the at least one sensed characteristic of the patient's cardiac cycle and determining at least one cardiac cycle parameter. In a further embodiment, the at least one cardiac cycle parameter is selected from the group consisting of an R-R interval, a P wave interval, a PR segment interval, a PQ segment interval, a QRS interval, an ST segment interval, and a QT interval, or an interbeat interval. The determined cardiac cycle parameter(s) may be used for synchronization of the stimulation and/or for determination of the duration of stimulation The external unit 270 may be a device that is capable of programming the IMD 200 with parameters defining the electrical signal. In one embodiment, the external unit 270 is a computer system capable of executing a data-acquisition program. The external unit 270 may be controlled by a healthcare provider, such as a physician, at a base station in, for example, a doctor's office, or via telemetry from a doctor's office to a patient's home. In alternative embodiments, the external unit 270 may be controlled by a patient in a system. In patient-controlled systems, the external unit 270 may provide less control over the operation of the IMD 200 than another external unit 270 controlled by a healthcare provider. Whether controlled by the patient or by a healthcare provider, the external unit 270 may be a computer, preferably a handheld computer or PDA, but may alternatively comprise any other device that is capable of electronic communications and programming, e.g., hand-held computer system, a PC computer system, a laptop computer system, a server, a personal digital assistant (PDA), an Apple-based computer system, etc. The external unit 270 may upload various parameters and program software into the IMD 200 for programming the operation of the IMD, and may also receive and download various status conditions and other data from the IMD 200. Communications between the external unit 270 and the communication unit 260 in the IMD 200 may occur via a wireless or other type of communication, represented generally by line 277 in FIG. 2. This may occur using, e.g., wand 155 (FIG. 1) to communicate by RF energy with a generator 110. Alternatively, the wand may be omitted in some systems, e.g., systems in which external unit 270 operates in the MICS bandwidths.

In one embodiment, the external unit 270 may comprise a local database unit 255. Optionally or alternatively, the external unit 270 may also be coupled to a database unit 250, which may be separate from external unit 270 (e.g., a centralized database wirelessly linked to a handheld external unit 270). The database unit 250 and/or the local database unit 255 are capable of storing various patient data. This data may comprise patient parameter data acquired from a patient's body and/or therapy parameter data. The database unit 250 and/or the local database unit 255 may comprise data for a plurality of patients, and may be organized and stored in a variety of manners, such as in date format, severity of disease format, etc. The database unit 250 and/or the local database unit 255 may be relational databases in one embodiment. A physician may perform various patient management functions using the external unit 270, which may include obtaining and/or analyzing data from the IMD 200 and/or data from the database unit 250 and/or the local database unit 255. The database unit 250 and/or the local database unit 255 may store various patient data.

One or more of the blocks illustrated in the block diagram of the IMD 200 in FIG. 2, may comprise hardware units, software units, firmware units, or any combination thereof Additionally, one or more blocks illustrated in FIG. 2 may be combined with other blocks, which may represent circuit hardware units, software algorithms, etc. Additionally, any number of the circuitry or software units associated with the various blocks illustrated in FIG. 2 may be combined into a programmable device, such as a field programmable gate array, an ASIC device, etc.

Pulse shapes in electrical signals according to the present invention may include a variety of shapes known in the art including square waves, biphasic pulses (including active and passive charge-balanced biphasic pulses), triphasic waveforms, etc. In one embodiment, the pulses comprise a square, biphasic waveform in which the second phase is a charge-balancing phase of the opposite polarity to the first phase.

Patient activation of an IMD 100 may involve use of an external control magnet for operating a reed switch in an implanted device, for example. Certain other techniques of manual and automatic activation of implantable medical devices are disclosed in U.S. Pat. No. 5,304,206 to Baker, Jr., et al., assigned to the same assignee as the present application (“the '206 patent”). According to the '206 patent, means for manually activating or deactivating the electrical signal generator 110 may include a sensor such as piezoelectric element mounted to the inner surface of the generator case and adapted to detect light taps by the patient on the implant site. One or more taps applied in fast sequence to the skin above the location of the electrical signal generator 110 in the patient's body may be programmed into the implanted medical device 100 as a signal for activation of the electrical signal generator 110. Two taps spaced apart by a slightly longer duration of time may be programmed into the IMD 100 to indicate a desire to deactivate the electrical signal generator 110, for example. The patient may be given limited control over operation of the device to an extent determined by the program dictated or entered by the attending physician. The patient may also activate the IMD 100 using other suitable techniques or apparatus.

In some embodiments, a cranial nerve stimulation system may include a sensing lead coupled at its proximal end to a header along with a stimulation lead and electrode assemblies. A sensor may be coupled to the distal end of the sensing lead. The sensor may include a cardiac cycle sensor. The sensor may also include a nerve sensor for sensing activity on a nerve, such as a cranial nerve, such as the vagus nerve 127.

In one embodiment, the sensor may sense a body parameter that corresponds to a symptom of a medical condition. If the sensor is to be used to detect a symptom of the medical condition, a signal analysis circuit may be incorporated into the IMD 100 for processing and analyzing signals from the sensor. Upon detection of the symptom of the medical condition, the processed digital signal may be supplied to a microprocessor in the IMD 100 to trigger application of the electrical signal to the cranial nerve, such as vagus nerve 127. In another embodiment, the detection of a symptom of interest may trigger a stimulation program comprising different stimulation parameters from a passive stimulation program. This may entail providing a higher current stimulation signal or providing a higher ratio of on-time to off-time.

FIG. 3A shows an exemplary instance of the cardiac cycle in a human being.

In one embodiment, the first point in the cardiac cycle is an R-wave and the second point in the cardiac cycle is the next R-wave, i.e., in this embodiment, the cardiac cycle is determined by an R-R interval and the interbeat interval is the R-R interval.

The interbeat interval can be determined from actual, particular cardiac data, or it can be calculated from actual, particular cardiac data. In one embodiment, the interbeat interval is a moving average R-R interval calculated over the last n R-R intervals, where n is an integer from 2 to about 100. The moving average can be a simple moving average, an exponential moving average, or another non-simple moving average, although a simple moving average is preferred. In a further embodiment, n is 3 in the calculation of the simple moving average.

The duration of applying can be less than, the same as, or greater than an interbeat interval of the patient. In one embodiment, the duration of applying is less than an R-R interval of the patient's cardiac cycle. In a further embodiment, the R-R interval is selected from the group consisting of an R-R interval immediately preceding the most recently detected R-wave, and a moving average R-R interval calculated over the last n R-R intervals, where n is an integer from 2 to about 100. In a further embodiment, n is 3.

The duration of applying may be determined from selected durations in a cardiac cycle of the patient, for example an ST segment duration, a PQ interval, or may comprise a percentage of an actual or calculated interbeat interval. In embodiments wherein the duration of applying is a percentage of an interbeat interval, the duty cycle of the IMD 200 may be a known ratio of on-time to off-time, which may be desirable in predicting useful battery life or device life. In one embodiment, the duration of applying is a percentage of the R-R interval, for example, from 0.1% of the R-R interval to 3000% or more of the R-R interval, or in a further embodiment, from 10% of the R-R interval to 50% of the R-R interval. The person of ordinary skill in the art will understand other cardiac periods could be the basis on which the duration of applying as a percentage thereof is calculated.

The electrical signal may be applied to the cranial nerve immediately after a predetermined point in the cardiac cycle or after a delay period following the predetermined point in the cardiac cycle. In this context, “immediately after” refers to less than ten microseconds after the IMD 200 detects the predetermined point in the cardiac cycle, e.g., an event selected from the group consisting of a P-wave, a Q-wave, an R-wave, an S-wave, a T-wave, and a U-wave, and processes the detection to yield a decision to apply the electrical signal.

When the electrical signal is applied after a delay period following the predetermined point in the cardiac cycle, the delay period can be from 0.1 msec to about 1000 msec.

In one illustrative embodiment, the electrical signal may be applied to the cranial nerve after a selected number of cardiac cycles. The selected number or cardiac cycles may be one (i.e., the electrical signal is applied during every cardiac cycle) or any integer greater than one. The IMD 200 may reselect the selected number of cardiac cycles during operation, for example, in response to data received regarding the patient's medical condition.

In another illustrative embodiment, the electrical signal may be applied to the cranial nerve after a selected length of clock time has passed. In one embodiment, the selected length of clock time is from 10 seconds to 30 minutes.

Embodiments of the present invention may also be combined with conventional neurostimulation in which the duration of the signal is independent of the cardiac cycle of the patient. For example, embodiments of the invention may be used to provide stimulation for short periods determined as a function of the cardiac cycle of the patient to allow the determination of moving averages of the patient's interbeat interval, and to provide stimulation bursts for much longer periods of time when the patient's cardiac cycle experiences rapid changes. For example, in epilepsy, many patients experience tachycardia (elevated heart rate) before or during a seizure. On the other hand, some epilepsy patients experience bradycardia (lowering of heart rate) before or during a seizure. In one embodiment, upon detecting tachycardia, the IMD 200 may apply an electrical stimulation for a predetermined time period that is independent of the cardiac cycle of the patient, for example 30 seconds, 1 minute, or shorter or longer fixed periods. In another embodiment, upon detecting bradycardia, the IMD 200 may likewise apply an electrical signal for a duration that is independent of the cardiac cycle of the patient. Neurostimulation independent of the cardiac cycle may be chosen to minimize the change in heart rate, the duration of the heart rate change, or both, in cases of tachycardia or bradycardia, but it need not be so chosen.

Turning now to FIG. 4, a flowchart depiction of a method 400 for treating a medical condition in accordance with one illustrative embodiment of the present invention is shown. An electrical signal generator is provided (block 410) and at least a first electrode is coupled to a cranial nerve of the patient and the electrical signal generator (block 420). The one or more electrodes may be operatively coupled to at least one of a main trunk of the right or left vagus nerve, or any branch thereof. The IMD may determine at least one cardiac cycle parameter, which may be selected from the group consisting of an R-R interval or another interbeat interval, a P wave interval, a PR segment interval, a PQ segment interval, a QRS interval, or an ST segment interval (block 430). The IMD 100 may then generate an electrical signal (block 440).

The IMD 100 may then apply the electrical signal to the cranial nerve (block 450). The application of the electrical signal may be delivered to the main trunk of the right or left vagus nerve, or any branch thereof The duration of applying is determined by the at least one cardiac cycle parameter of the patient.

Using embodiments of the present invention, a therapeutic regimen comprising neurostimulation may be enhanced and optimized. Using certain embodiments, data either directly or indirectly associated with an acute incident of a medical condition may be collected, in order to inform the patient and/or his physician about the severity, progression, or remission of the medical condition.

All of the methods and apparatuses disclosed and claimed herein may be made and executed without undue experimentation in light of the present disclosure. While the methods and apparatus of this invention have been described in terms of particular embodiments, it will be apparent to those skilled in the art that variations may be applied to the methods and apparatus and in the steps, or in the sequence of steps, of the method described herein without departing from the concept, spirit, and scope of the invention, as defined by the appended claims. It should be especially apparent that the principles of the invention may be applied to selected cranial nerves other than, or in addition to, the vagus nerve to achieve particular results in treating patients having epilepsy, depression, or other medical conditions.

The particular embodiments disclosed above are illustrative only as the invention may be modified and practiced in different but equivalent manners apparent to those skilled in the art having the benefit of the teachings herein. Furthermore, no limitations are intended to the details of construction or design herein shown other than as described in the claims below. It is, therefore, evident that the particular embodiments disclosed above may be altered or modified and all such variations are considered within the scope and spirit of the invention. Accordingly, the protection sought herein is as set forth in the claims below. 

1. A method of providing an electrical signal to a cranial nerve of a patient for treating a medical condition, comprising: providing an electrical signal generator, coupling at least a first electrode to a cranial nerve of the patient and to the electrical signal generator, generating an electrical signal with the electrical signal generator, and applying the electrical signal to the cranial nerve, using the at least a first electrode, for a duration determined by a cardiac cycle parameter of the patient.
 2. The method of claim 1 wherein applying the electrical signal to the cranial nerve comprises applying the electrical signal for a duration determined by at least one of an R-R interval, a P-P interval, a T-T interval, a P wave interval, a PR segment interval, a PQ segment interval, a QRS interval, an ST segment interval, and an interbeat interval of the patient.
 3. The method of claim 2 wherein the duration of applying is less than the interbeat interval.
 4. The method of claim 3, wherein the duration is determined by reference to an interbeat interval selected from the group consisting of an R-R interval immediately preceding the most recently detected R-wave, and a moving average R-R interval calculated over the last n R-R intervals, where n is an integer from 2 to about
 10. 5. The method of claim 4, wherein n is
 3. 6. The method of claim 1, wherein the duration of applying is a percentage of the interbeat interval.
 7. The method of claim 6, wherein the duration of applying is from 0.1% of the interbeat interval to 3000% of the interbeat interval.
 8. The method of claim 7, wherein the duration of applying is from 10% of the interbeat interval to 50% of the interbeat interval.
 9. The method of claim 1, wherein applying the electrical signal to the cranial nerve comprises beginning to apply the electrical signal at a particular point in the cardiac cycle of the patient.
 10. The method of claim 9, wherein the particular point in the cardiac cycle is selected from the group consisting of a detected P-wave, a detected Q-wave, a detected R-wave, a detected S-wave, a detected T-wave, and a detected U-wave.
 11. The method of claim 9, wherein the particular point in the cardiac cycle follows a point in the cardiac cycle selected from the group consisting of a detected P-wave, a detected Q-wave, a detected R-wave, a detected S-wave, a detected T-wave, and a detected U-wave by a delay period.
 12. The method of claim 11, wherein the delay period is from 0.1 msec to about 1000 msec.
 13. The method of claim 1, wherein applying the electrical signal to the cranial nerve comprises beginning to apply the electrical signal after a selected number of occurrences of at least one characteristic of the patient's cardiac cycle selected from the group consisting of a detected P-wave, a detected Q-wave, a detected R-wave, a detected S-wave, a detected T-wave, and a detected U-wave.
 14. The method of claim 13, wherein applying the electrical signal to the cranial nerve comprises beginning to apply the electrical signal after a predetermined number of R-waves ranging from two R-waves to 1000 R-waves.
 15. The method of claim 1, further comprising: sensing at least one parameter of a cardiac cycle of the patient selected from the group consisting of a P-wave, a Q-wave, an R-wave, an S-wave, a T-wave, and a U-wave, and providing a cardiac cycle determination module to analyze the at least one sensed parameter of the patient's cardiac cycle and to determine said at least one cardiac cycle parameter.
 16. The method of claim 2 wherein the duration of applying is greater than the interbeat interval.
 17. In a method of applying an electrical signal to a cranial nerve of a patient for treating a medical condition, the improvement comprising: applying the electrical signal to the cranial nerve, wherein applying said electrical signal is provided for a duration determined by a cardiac cycle parameter of the patient.
 18. An implantable medical device (IMD), comprising: an electrical signal generator; a first electrode operatively coupled to the electrical signal generator; and a cardiac cycle determination module capable of determining at least one cardiac cycle parameter of a patient; wherein: the electrical signal generator is capable of generating and delivering at least one electrical signal through the first electrode, wherein said electrical signal is delivered for a duration determined by the cardiac cycle parameter of the patient.
 19. The implantable medical device of claim 18, wherein the electrical signal generator is capable of generating and delivering the at least one electrical signal through the first electrode, and wherein said electrical signal is initiated at a time determined by the at least one cardiac cycle parameter and for a duration determined by the at least one cardiac cycle parameter. 